Vascular cognitive impairment (VCI), including vascular dementia and vascular mild cognitive impairment, is a common complication of stroke and the second leading cause, following Alzheimer disease (AD), of dementia which has made huge impacts on the patients, families and society. Currently, there is no effective treatment for VCI. The recent, clinical observation studies revealed that CVI is not only the consequences of indicated stroke events, or acute brain injury, but also presents a chronic disease course. Patients usually experience continuous decline of cognition even without another stroke event. Ischemic stroke might trigger some neuro-degenerative processes in addition to the episodic acute ischemic brain injury. Amyloid accumulation and chronic neuro-inflammation, resulting in hippocampal atrophy and white matter damage have been recognized as two main mechanisms for VCI, especially for the late deterioration of cognitive function. However, the real molecular machinery, including the role of amyloid accumulation and the precise inflammation signaling pathway attributed to VCI is still largely unknown. In this study, we will establish a VCI mouse model with bilateral common carotid artery occlusion (BCCAO) in wild type and AD (APP/PS1 mutation) mice. The roles of amyloid accumulation and neuro-inflammation will be explored in this model. We will measure senile plaques by amyloid PET, hippocampal atrophy and white matter damage by 7T-animal MRI and phosphorylated Tau by immunohistochemistry. Tau conferring interaction with amyloid is also a landmark of AD and considered to be involved in pathogenesis of VCI. The compelling evidence has shown high mobility group box 1 (HMGB1) is involved in amyloid formation and neuro-inflammation in bother AD and stroke. Therefore, high mobility group box 1 (HMGB1)-related pathway which includes toll-like receptors (TLRs), receptor for advanced glycosylation endproducts (RAGE) and their downstream molecules will be explored. This study will provide molecular mechanisms of VCI in the animal model and novel anti-amyloid, anti-neuro-inflammation therapy could be developed in the future.
|Effective start/end date||8/1/17 → 7/31/18|
- vascular cognitive impairment